In the past year we have collaborated with labs that have produced knock-out models of the KSR1 and KSR2 genes and the ANKR26 genes. These three genes were knocked out to determine their role in oncogenesis, but an unexpected feature of the knock-out animal was an obese phenotype. In addition to these 3 genes, we are also currently studying a human orexin gene receptor (HCRTR2) that has a role in energy metabolism in mice as well as the WDTC1 gene that regulates fat accumulation in mice. All of these genes have been directly sequenced in DNA samples from Pima Indians and all variants have been genotyped for assocation studies. We were able to confirm in humans, as observed in mice, that variation within KSR2 is associated with decreased energy expenditure (both as measured in a human respiratory chamber and a ventilated hood) and decreased physical activity (as measured by radar over 24 hours in a respiratory chamber). In contrast, we did not obeserve variantion in KSR1 that altered energy expenditure or predicted obesity in humans. Variation in ANKR26 does not appear to contribute to the high prevalence of obesity in Pima Indians, however, we are currently analyzing variation in this gene in discordant Caucasian sibling pairs where genetic linkage to body mass index was previously observed in the genomic region that encompasses the ANKR26 gene. Studies with human HCRTR2 and WDTC1 are ongoing.